Inhibition of IKr potentiates development of atrial-selective INa block leading to effective suppression of atrial fibrillation.

Abstract

The availability of safe and effective drugs for the management of atrial fibrillation (AF) remains an unmet medical need. The purpose of this study was to test the hypothesis that the inhibition of the rapidly activating delayed rectifier potassium current (IKr) greatly potentiates the development of atrial-selective sodium channel current (INa) block, leading to more effective suppression of AF. Electrophysiological and anti-AF effects of highly selective INa and IKr blockers (lidocaine and E-4031) individually and in combination were determined in canine coronary-perfused atrial and ventricular preparations. Acetylcholine (1 µM) was used to induce persistent AF. Lidocaine (10 µM) caused a relatively small abbreviation of the action potential duration measured at 90% repolarization in both atria and ventricles, but caused atrial-selective prolongation of the effective refractory period owing to the induction of post-repolarization refractoriness. Lidocaine also caused modest atrial-selective depression of other INa-mediated parameters including excitability, maximum rate of rise of the action potential upstroke, and conduction time. E-4031 (1 µM) prolonged the action potential duration measured at 90% repolarization and effective refractory period in an atrial-predominant manner. A combination of lidocaine and E-4031 caused a greater atrial-selective depression of INa-mediated parameters. Persistent acetylcholine-mediated AF developed in 100% of atria under control conditions, in 80% (4 of 5) after pretreatment with lidocaine (10 µM), in 100% (4 of 4) after E-4031 (1 µM), and in only 14% (1 of 7) after the combination of lidocaine and E-4031. Our results provide a proof of concept that IKr block greatly potentiates the effects of rapidly dissociating INa blockers to depress sodium channel-dependent parameters in the canine atria but not in the ventricles, thus contributing significantly to suppression of AF.